This invention relates to a process for the preparation of thebaine and analogues thereof, and to a novel intermediate useful in such a process. In particular, the invention relates to the preparation of thebaine from N-methyl morphinans, its isolation as a salt and the use of the salt in the preparation of N-methyl-14-hydroxymorphinones.
Thebaine is an N-methylmorphinan having the structure (A): 
Thebaine and analogous compounds containing a dienol ether or a dienol ester are useful intermediates in the preparation of 14-hydroxymorphinans, such as oxycodone, naltrexone, nalbuphine and naloxone. Oxycodone is the corresponding 14-hydroxy-N-methylmorphinone (also called 14-hydroxy-7,8-dihydrocodeinone) having the structure (B): 
Unfortunately, thebaine is expensive and is not always readily available in industrially-required quantities. Sohar et al, U.S. Pat No. 3,894,026, disclose a method for producing thebaine, but the starting material is salutaridinol, which is itself not readily available. Therefore, it is desirable to prepare thebaine or its analogues, directly or through known intermediates, from more readily available morphinans such as codeine and morphine. Codeine is the corresponding 6-OH monoenolether analogue of thebaine.
Rapoport et al, U.S. Pat No. 4,045,440, provide a method for producing thebaine from codeine via the intermediate codeine methyl ether. This method requires a 90-second reaction time in preparation of the intermediate, and is thus not suitable for use on an industrial scale. The method also requires a 24-hour reaction period for conversion of the intermediate to thebaine, and employs a heterogeneous catalyst, manganese dioxide, for the transformation, leading to further difficulties on scale-up.
Schwartz, U.S. Pat Nos. 4,472,253 and 4,795,813 and J. Med. Chem. 24,1525 (1981) provides a method for producing certain dienol ester analogues of thebaine having the structural formula (C): 
wherein R11 is lower alkyl, R12 is cyano or acyl, and R13 is acyl. These thebaine analogues, in which the N-methyl group has been replaced by R12, are useful as intermediates for naloxone, naltrexone and nalbuphine, but are not useful as intermediates to 14-hydroxy-morphinan compounds having an N-methyl group, such as oxycodone or oxymorphone. For these compounds, thebaine is the desired intermediate, since it has the required N-methyl substituent.
Further, the method of Schwartz, which employs a reaction temperature of 80-100xc2x0 C. to introduce the R12 acyl group, may not readily be extended to preparation of an N-methyl dienol ester, since at such a temperature, the N-methyl group would also be acylated, leading to by-products and reduced yield. Extension of this method to the preparation of N-methyl dienol ether compounds, such as thebaine, is also not feasible. At the reaction temperatures employed to introduce R12, not only would the N-methyl group be alkylated, leading to by-products and reduced yield, but the alkylating agent would be destroyed by reaction with the base employed in the process.
Wallace, U.S. Pat No. 5,112,975, employs a process similar to that of Schwartz to prepare compounds of structural formula (C), but wherein the R13 is an alkoxycarbonyl substituent. This process differs from that disclosed by Schwartz in that the ultimate starting material is morphine, rather than codeine, but has limited use as a method for preparing thebaine or thebaine analogues with N-alkyl substitution for the same reasons given in the preceding paragraph.
British patent number 1,260,699 discloses a method for preparation from codeine of dienol ethers analogous to thebaine. However, the method used for isolation of these dienol ethers is lengthy, requiring a chromatographic separation, and gives a low yield of the product. For these reasons, this method is not useful for large-scale preparation of thebaine.
It has now been found possible to provide an efficient, high-yielding process for the preparation of thebaine or thebaine analogues (i.e. having N-CH3 substitution) containing a dienol ester or a dienol ether, from morphinone, codeinone or analogues thereof which contain an a,xcex2-unsaturated ketone via a novel alkoxylated intermediate.
Accordingly, the present invention provides a process for the preparation of a compound of formula (I) or salt thereof: 
wherein R1 and R3are the same or different and each is a protecting group; and
R2 is lower alkyl, allyl or lower alkyl substituted by cycloalkyl; said process comprising the reaction of the compound of formula (III): 
wherein R1 and R2 are as hereinbefore defined; and
M is an alkali metal or a quaternary ammonium cation;
with a compound of formula R3X, wherein R3 is as hereinbefore defined and X is a leaving group; and, optionally, but preferably,
the reaction of the compound of formula (I) so prepared with an acid, such as L-tartaric acid, to give a salt, such as the bitartrate, of the compound of formula (I).
Preferred protecting groups in the definition of R1 and R3 are selected from alkyl or acyl groups. Preferred alkyl groups are selected from lower alkyl, trialkylsilyl, alkyldiarylsilyl and acyl, although they may also be selected from aryl and alkylaryl, any of which alkyl and aryl groups may be substituted by halo. Preferred aryl groups are phenyl. Preferred acyl groups are selected from those of formula R4COxe2x80x94, wherein R4 is selected from lower alkyl, lower alkyl substituted by halo or phenyl, and aryl, such as phenyl and substituted phenyl. R4 is preferably selected from lower alkyl, phenyl or substituted phenyl. Preferably, alkyl groups herein have from 1-6, more preferably 1-4, carbon atoms; and aryl groups herein are phenyl, optionally substituted by alkyl and/or halo, such as chloro.
In an especially preferred aspect of the present invention, the compounds prepared by the above process are compounds of formula (I) wherein R1, R2 and R3 may be the same or different and each is lower alkyl, for example C1-6 alkyl, such as C1-4 alkyl and preferably methyl or ethyl. In a particularly preferred aspect, the compound prepared is thebaine or a salt thereof, preferably the bitartrate salt.
Suitable agents R3X used in the preparation of the compounds of formula (I) include those alkylating or acylating agents where R3 is preferred as defined hereinbefore. Suitable leaving groups X are halo, alkanoate, benzoate, substituted benzoate, alkyl sulphate, alkyl sulphonate, aryl sulphate, arylsulphonate, halosulphonate, haloalkylsulphonate, tetra-alkylammonium halide and dialkyl phosphate. Therefore, suitable alkylating agents R3X include dimethyl sulphate, diethyl sulphate, dibutyl sulphate, methyl methanesulphonate, methyl trifluoromethane sulphonate, alkylarylsulphonates, trialkylphosphates and trialkylsilyl chlorides. Preferably, the alkylating agent is dimethyl sulphate or diethyl sulphate.
Suitable acylating agents, R3X, include acetic anhydride, propionic anhydride, acetyl chloride, propionyl chloride, and carboxylic acid anhydrides or halides derived from other alkyl or aryl carboxylic acids.
The alkylation/acylation is satiably carried out at a temperature of from xe2x88x9240xc2x0 C. to +30xc2x0 C. Although reaction at a higher temperature would produce the desired compound, alkylation or acylation of the tertiary nitrogen of the starting compound (a compound of formula (III)) or of the product (a compound of formula (I)) or of both may occur, leading to by-products and an accompanying yield loss, as previously mentioned.
The optional salt formation is carried out by dissolving the compound of formula (I) in a suitable solvent, which may be selected from those in which the salt to be formed is insoluble or from which it is capable of recrystallising, and thereafter treating the resulting solution with the corresponding acid, 1o such as tartaric acid, other organic acids, or inorganic acids such as hydrochloric acid, hydrobromic acid or perchloric acid, optionally at elevated temperature. Preferably, the bitartrate salt is formed by dissolving the compound of formula (I) in a suitable solvent, such as toluene or methanol, and treating the resulting solution with L-tartaric acid at a temperature of, for is example, 20-60xc2x0 C. The bitartrate salt of the compound of formula (I) so formed may be further purified by crystallisation from, for example, aqueous methanol or ethanol.
The bitartrate salts of the compounds of formula (I) thereby prepared, particularly thebaine bitartrate, may then be used in the preparation of the corresponding 14-hydroxymorphinones, particularly oxycodone. It has surprisingly been found that the bitartrate salts, which generally include some water of hydration (e.g. thebaine bitartrate monohydrate), can be purified to the extent required for pharmaceutical grade 14-hydroxymorphinone analogues (e.g. oxycodone) to be prepared.
The conversion of the bitartrate salt to the 14-hydroxymorphinone analogue is preferably accomplished by a method analogous to that described herein in Example 8, comprising oxidation/dealkylation or deacylation followed by hydrogenation.
Accordingly, the present invention provides the use of a salt, preferably the bitartrate salt, of a compound of formula (I) as defined hereinbefore in the purification and/or preparation of a corresponding 14-hydroxymorphinone. Most preferred is the use of thebaine bitartrate in the preparation of oxycodone.
Compounds of formula (III) are novel and, accordingly, a still further aspect of the present invention provides a compound of formula (III) as hereinbefore defined. Preferred compounds of formula (III) are those wherein R1, R2 and M have the values described as preferred in the description above. Especially preferred is when R1 and R2 are both methyl, such as a derivative of thebaine or an analogue thereof, having a dienol ester or ether. Most preferred is when M is potassium, sodium or lithium, especially potassium.
Accordingly, the present invention further provides a process for the preparation of a compound of formula (III) as hereinbefore defined, which process comprises the reaction of a compound of formula (II): 
wherein R1 and R2 are as defined for formula (III), with an alkoxide base of formula MOR, wherein M is as defined for formula (III) and R is alkyl.
The reaction is suitably carried out in a solvent which will not react with the alkoxide base, but which readily dissolves both the base and the compound of formula (II), such as a dipolar aprotic solvent. Examples of such solvents are N-methylpyrrolidinone, N-methylcaprolactam, dimethyl sulphoxide, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,3-dimethyl-3,4,5,6-tetrahydro-2(IH)-pyrimidinone, and mixtures of these solvents with each other or with one or more aromatic hydrocarbon solvent(s), such as toluene. The preferred solvent is N-methylpyrrolidone.
The reaction is suitably carried out at a temperature ranging from xe2x88x9280xc2x0 C to +60xc2x0 C. Preferably, a dilute solution of the compound of formula (II) is added slowly to a solution of the base in order to minimise self-condensation. Preferred bases for this step include metal oxides, such as potassium tert-butoxide, potassium tert-pentoxide, sodium tert-butoxide or lithium tert-butoxide.
The invention will now be further described with reference to the following examples which are intended to illustrate but not limit the invention. The purity of the products of the examples was determined by reverse phase HPLC using the Waters Symmetry 4.6-100 mm C-18 3.5 xcexcm column and the gradient method with water/acetonitrile as the mobile phase. The NMR spectra were run using a 300 MHz FT spectrometer.